Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer

Dohnal, Alexander; Witt, Volker; Hügel, Heino; Holter, Wolfgang; Gadner, Helmut; Felzmann, Thomas

doi:10.1080/14653240701589221

Cited by 64 publications

(73 citation statements)

References 45 publications

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“…16 In rodents with minimal disease, CTL adoptive transfer also has not been uniformly curative despite the early transfer of large numbers of anti-AML-reactive CTLs. 17,18 Enhancing CTL function in vivo via the administration of supportive cytokine therapy such as interleukin-2 (IL-2), 19 IL-12, 20 and interferons 21 can improve antitumor efficacy but has been associated with substantial side effects. Therefore, recent studies have focused on eliminating the suppressive factors in the tumor environment to circumvent CTLs from inhibition.…”

Section: Introductionmentioning

confidence: 99%

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Zhou

Bucher

Munger

et al. 2009

Blood

132

113

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IntroductionAcute myeloid leukemia (AML) with unfavorable cytogenetics has a poor outcome, even when treated with aggressive chemotherapy. 1,2 With chemoradiotherapy and hematopoietic stem cell transplantation, a graft-versus-leukemia effect can be observed even in patients with unfavorable cytogenetics. 3 Although donor lymphocyte infusion (DLI) given as adoptive immunotherapy after hematopoietic stem cell transplantation has improved the outcomes of certain types of leukemia, 4-6 for patients with AML, DLI has been less effective likely due at least in part to its rapid tumor progression. 7,8 As a result of the anti-AML effects of DLI and with the observation that antitumor-specific cytotoxic T cells (CTLs) can be generated in vitro from cancer patients, adoptive CTL therapy has been proposed for decades as cancer treatment. [9][10][11][12][13][14] However, the adoptive transfer of anti-AML-reactive CTLs alone has not solved the problem of AML disease recurrence. 15 In patients with chronic myelogenous leukemia, a complete remission was achieved in a patient with accelerated-phase disease after adoptive treatment with leukemia-reactive CTLs. 16 In rodents with minimal disease, CTL adoptive transfer also has not been uniformly curative despite the early transfer of large numbers of anti-AML-reactive CTLs. 17,18 Enhancing CTL function in vivo via the administration of supportive cytokine therapy such as interleukin-2 (IL-2), 20 and interferons 21 can improve antitumor efficacy but has been associated with substantial side effects. Therefore, recent studies have focused on eliminating the suppressive factors in the tumor environment to circumvent CTLs from inhibition. 22,23 T-regulatory cells (Tregs) are important regulators of immune responses in transplantation, 24,25 allergy, 26,27 and autoimmune disease. 28,29 In AML patients, the frequency of Tregs was noted to be significantly higher compared with healthy persons, likely due to increased proliferation. 30 Human AML cells have been noted to favor the conversion of CD4 ϩ 25 Ϫ T cells into Tregs via modulation of tryptophan catabolism. 31 Tregs that have been recruited to, or converted either before migration into or within the tumor environment, can have a profound inhibition on T cell-mediated immune response. 32 Multiple mechanisms have been defined to be responsible for the suppression, including secretion of transforming growth factor-␤ 33,34 and IL-10, 33,34 as well as inhibition of dendritic cell (DC) maturation. 33,35 Despite the great potential for Treg depletion in cancer therapies, the efficacy has been limited to prophylactic settings where depletion of Tregs is given before the establishment of tumor. 36,37 The present studies were undertaken to determine whether endogenous Tregs present at the site of AML dissemination constrained the antileukemia efficacy of anti-AML CTL adoptive transfer in a rodent model as a prelude to future clinical trials. We observed that AML progression correlated with increased Tregs at the sites of AML disease. Incr...

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Section: Introductionmentioning

confidence: 99%

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Zhou

Bucher

Munger

et al. 2009

Blood

132

113

View full text Add to dashboard Cite

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“…Dendritic cell based therapeutic approach has now been applied as an adjuvant for the treatment of several types of cancers such as lymphomas (Hsu et al 1996), myelomas (Curti et al, 2007), brain cancers (Ardon et al, 2012) and pediatric malignancies (Dohnal et al, 2007) with some degree of success. Since no uniform standardised protocol has emerged, we developed a protocol and initiated a phase I trial.…”

Section: Discussionmentioning

confidence: 99%

Development and Clinical Evaluation of Dendritic Cell Vaccines for HPV Related Cervical Cancer - a Feasibility Study

Ramanathan¹,

Ganesarajah²,

Raghanvan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Human papillomavirus infection (HPV) and HPV related immune perturbation play important roles in the development of cervical cancer. Since mature dendritic cells (DCs) are potent antigen-presenting cells (APC), they could be primed by HPV antigens against cervical cancers. In this study we were able to generate, maintain and characterize, both phenotypically and functionally, patient specific dendritic cells in vitro. A randomized Phase I trial with three arms -saline control (arm I), unprimed mature DC (arm II) and autologous tumor lysate primed mature DC (arm III) and fourteen patients was conducted. According to WHO criteria, grade 0 or grade one toxicity was observed in three patients. One patient who received tumor lysate primed dendritic cells and later cis-platin chemotherapy showed a complete clinical response of her large metastatic disease and remained disease free for more than 72 months. Our findings indicate that DC vaccines hold promise as adjuvant sfor cervical cancer treatment and further studies to improve their efficacy need to be conducted.

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“…Другая группа исследователей использовала комбинацию ЛПС (200 ед/мл) и ИФН-g (50 нг/мл) в качестве коктейля для получения зрелых ДК [42]. В качестве критерия оценки ДК, который определяет эффективность ДК как компонента противораковых вакцин, было предложено использовать концентрацию ИЛ-12p70, продуцируемого 1 млн клеток за 24 ч которая должна составлять не менее 100 пг/мл среды.…”

Section: индукция созревания дендритных клетокunclassified

Preparation of dendritic cells for cancer immunotherapy

Nazarkina

Laktionov

2015

BIOMED KHIM

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Development of new effective method for cancer therapy is one of the most important trends in the modern medicine. Along with surgery, chemotherapy and radiotherapy, induction of an immune response against the tumor cells is a promising approach for therapy of cancer, particularly metastatic, slowly dividing tumors and cancer stem cells. Induction of the antitumor T-cell immune response involves activation of antigen-presenting cells, which can efficiently present the cancer antigens and activate T-lymphocytes. The immune response may be activated by dendritic cells (DC) loaded with tumor antigens, such as tumor-specific proteins, tumor cell lysates, apoptotic or necrotic tumor cells, as well as nucleic acids encoding tumor antigens. Regardless of the selected source of the tumor antigen, preparation of mature DC is a principal step in the development of anticancer vaccines aimed at the induction of the cytotoxic T-cell immune response. Recently, various research groups have proposed several strategies for producing mature DC, differed by the set of agents used. It has been shown that the maturation strategy influences both their phenotype and the ability to induce the immune response. In this review we have analyzed the results of studies on the various strategies of preparation of mature DCs.

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Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer

Cited by 64 publications

References 45 publications

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Development and Clinical Evaluation of Dendritic Cell Vaccines for HPV Related Cervical Cancer - a Feasibility Study

Preparation of dendritic cells for cancer immunotherapy

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